Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome.
نویسندگان
چکیده
Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.
منابع مشابه
Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion.
arl13b was initially cloned as the novel cystic kidney gene scorpion (sco) in zebrafish and was shown to be required for cilia formation in the kidney duct. In mouse, a null mutant of Arl13b shows abnormal ultrastructure of the cilium and defective sonic hedgehog (Shh) signaling. Importantly, a recent study linked mutations in ARL13B to a classical form of Joubert syndrome (JS), an autosomal re...
متن کاملStructural insights into the small G-protein Arl13B and implications for Joubert syndrome.
Ciliopathies are human diseases arising from defects in primary or motile cilia. The small G-protein Arl13B (ADP-ribosylation factor-like 13B) localizes to microtubule doublets of the ciliary axoneme and is mutated in Joubert syndrome. Its GDP/GTP mechanistic cycle and the effect of its mutations in patients with Joubert syndrome remain elusive. In the present study we applied high resolution s...
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Arl13b belongs to the ADP-ribosylation factor family within the Ras superfamily of regulatory GTPases. Mutations in Arl13b cause Joubert syndrome, which is characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. Arl13b is highly enriched in cilia and is required for ciliogenesis in multiple organs. Nevertheless, the precise role of Arl13b remains el...
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Small G-proteins of the ADP-ribosylation-factor-like (Arl) subfamily have been shown to be crucial to ciliogenesis and cilia maintenance. Active Arl3 is involved in targeting and releasing lipidated cargo proteins from their carriers PDE6δ and UNC119a/b to the cilium. However, the guanine nucleotide exchange factor (GEF) which activates Arl3 is unknown. Here we show that the ciliary G-protein A...
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The regulatory GTPase Arl13b localizes to primary cilia, where it regulates Sonic hedgehog (Shh) signaling. Missense mutations in ARL13B can cause the ciliopathy Joubert syndrome, while the mouse null allele is embryonic lethal. We used mouse embryonic fibroblasts as a system to determine the effects of Arl13b mutations on Shh signaling. We tested a total of seven different mutants, three JS-ca...
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ورودعنوان ژورنال:
- American journal of human genetics
دوره 83 2 شماره
صفحات -
تاریخ انتشار 2008